NM_002693.2(POLG):c.3640C>T (p.Gln1214Ter) AND Progressive sclerosing poliodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Jun 28, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000758431.2

Allele description [Variation Report for NM_002693.2(POLG):c.3640C>T (p.Gln1214Ter)]

NM_002693.2(POLG):c.3640C>T (p.Gln1214Ter)

Gene:
POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q26.1
Genomic location:
Preferred name:
NM_002693.2(POLG):c.3640C>T (p.Gln1214Ter)
HGVS:
  • NC_000015.10:g.89317379G>A
  • NG_008218.2:g.22417C>T
  • NG_011736.1:g.78417G>A
  • NM_001126131.2:c.3640C>T
  • NM_002693.2:c.3640C>T
  • NP_001119603.1:p.Gln1214Ter
  • NP_002684.1:p.Gln1214Ter
  • LRG_765t1:c.3640C>T
  • LRG_500:g.78417G>A
  • LRG_765:g.22417C>T
  • LRG_765p1:p.Gln1214Ter
  • NC_000015.9:g.89860610G>A
Protein change:
Q1214*
Links:
dbSNP: rs781256643
NCBI 1000 Genomes Browser:
rs781256643
Molecular consequence:
  • NM_001126131.2:c.3640C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_002693.2:c.3640C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Progressive sclerosing poliodystrophy (MTDPS4A)
Synonyms:
Alpers disease; Alpers diffuse degeneration of cerebral gray matter with hepatic cirrhosis; Alpers progressive infantile poliodystrophy; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008758; MedGen: C0205710; Orphanet: 726; OMIM: 203700

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000887135Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicinecriteria provided, single submitter
Pathogenic
(Oct 1, 2018)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001506455Invitaecriteria provided, single submitter
Uncertain significance
(Jun 28, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum.

Tang S, Wang J, Lee NC, Milone M, Halberg MC, Schmitt ES, Craigen WJ, Zhang W, Wong LJ.

J Med Genet. 2011 Oct;48(10):669-81. doi: 10.1136/jmedgenet-2011-100222. Epub 2011 Aug 31.

PubMed [citation]
PMID:
21880868
See all PubMed Citations (3)

Details of each submission

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV000887135.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The NM_002693.2:c.3640C>T (NP_002684.1:p.Gln1214Ter) [GRCH38: NC_000015.10:g.89317379G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PVS1:This variant is a predicted null variant in POLG where loss of function is a known mechanism of disease. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PM4:This variant causes alteration in the length of expressed protein. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001506455.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change results in a premature translational stop signal in the POLG gene (p.Gln1214*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acids of the POLG protein. This variant is present in population databases (rs781256643, ExAC 0.001%). This variant has been observed in individual(s) with autosomal recessive progressive external ophthalmoplegia (PMID: 21880868). ClinVar contains an entry for this variant (Variation ID: 488798). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 17, 2021

Support Center